This proposal investigates the roles of reactive oxgyen species and NAD(P)H oxidases in cardiac fibrosis induced by angiotensin II. NAD(P)H oxidases are the major sources of reactive oxygen species in cardiovascular cells. Previous work in this laboratory has shown that angiotensin II stimulates in vitro the production of reactive oxygen species and upregulates NAD(P)H expression in the pathophysiology of cardiac fibrosis. The transformation of fibroblasts to myofibroblasts represents a key process in cardiac fibrosis. This proposal addresses the following specific aims: 1) Determine whether an NAD(P)H oxidase mediates the transformation of fibroblasts into myofibroblasts by angiotensin II in vitro, and 2) Establish the role of NAD(P)H oxidases in mouse models of cardiac hypertrophy and fibrosis produced by chronic infusion of angiotensin II. Elucidation of the mechanisms by which cardiac fibroblasts transform into myofibroblasts during cardiac fibrosis will provide insight into the pathophysiology of human hypertensive heart disease and enable future development of specific inhibitors of adverse myocardial remodeling.